PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC), which accounts for 85% of pancreatic cancer, is one of the most lethal cancers with limited therapeutic options. Epigenetic therapy holds tremendous promise in cancer therapeutics. It depends on small molecules that can modulate chromatin status thereby altering disease phenotypes. Developing novel epigenetic therapy tailored for PDAC treatment will open up unprecedented possibility for improving patient survival and life quality. However, so far, the potential of epigenetic drugs for treating PDAC remains to be fully explored. Through screening of a panel of epigenetic drugs, histone deacetylase (HDAC) inhibitor MS275 (MS, also called entinostat) has been shown to have potent anti-PDAC effects. MS not only suppresses tumor cell proliferation but also inhibits the activation of stromal pancreatic stellate cells (PSCs) in vitro and in vivo. This project aims to investigate how MS regulates the tumor cell and stromal compartments in PDAC, and to comprehensively assess the therapeutic potential of MS with animal models. To achieve these aims, an experimental platform based on orthotopic transplantation and fluorescence-activated cell sorting (FACS) is established for isolating cells of individual PDAC compartments from in vivo developed tumors. Aim 1 of the proposal will define the molecular mechanism underlying the anti- proliferative effect of MS on tumor cells, focusing on its role in regulating gene expression and the epigenomes. Aim 2 will investigate how MS inhibits PSC activation and how it affects immune cell infiltration in the tumor microenvironment. Aim 3 will assess the therapeutic potential of MS as a single agent or in combination with chemotherapy and/or immune check point therapy, using orthotopic transplantation and genetically engineered mouse model (GEMM) of PDAC. It will also evaluate the potential of MS for treating or preventing chronic pancreatitis, a disease condition involving PSC activation and predisposing to PDAC. Completion of the proposed studies will not only establish novel epigenetic therapy for pancreatic cancer, but also reveal the mechanisms contributing to its therapeutic benefit.